EP0125139A2 - Spezifische Bindungsagenzein verwendende Testverfahren - Google Patents
Spezifische Bindungsagenzein verwendende Testverfahren Download PDFInfo
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- EP0125139A2 EP0125139A2 EP84303090A EP84303090A EP0125139A2 EP 0125139 A2 EP0125139 A2 EP 0125139A2 EP 84303090 A EP84303090 A EP 84303090A EP 84303090 A EP84303090 A EP 84303090A EP 0125139 A2 EP0125139 A2 EP 0125139A2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
- A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/6848—Needles
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/004—Enzyme electrodes mediator-assisted
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6816—Hybridisation assays characterised by the detection means
- C12Q1/6825—Nucleic acid detection involving sensors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
- G01N33/5438—Electrodes
Definitions
- This invention generally relates to assay techniques and especially to the detection measuring and monitoring of complex, usually biologically-arising, molecules or part-molecular structures often in complicated admixture with other similar molecules.
- the techniques of this invention utilise specific binding agents, i.e. complex molecular species which have a specific reaction, usually based on electrostatic or hydrophobic forces, with one or more active sites on a given type of molecule only.
- One limb of this invention is concerned with immunoassay techniques to be carried out in vivo or in vitro i.e. those techniques in which large antibody or antigen molecules, naturally present in or artificially induced to appear in a body fluid such as plasma, serum, whole blood, urine, interstitial fluid, cerebrospinal fluid or synovial fluid (or made as monoclonal antibodies) are reacted with usually smaller, specifically-reacting ligand molecules.
- these ligands include species which are not per se antigenic, but may be made so by crosslinking them to a suitable carrier.
- Another limb of the present invention is concerned with; firstly techniques for investigating DNA or RNA sequencing i.e.
- the two limbs of the invention will be jointly referred to as specific binding reactions between ligands and antiligands.
- the invention further relates to equipment or materials useful in the above techniques, either as such or possibly as usable coordinated kits of parts.
- RNA probe techiques share a similarity in that the DNA (RNA) polymer is not readily detectable by its inherent biochemical activity. It is therefore necessary to mark the polymer with some signal-producing chemical or biochemical species, such methods include:-
- the present invention sets out to overcome the above disadvantages by utilising simple electrochemical measurement techniques, and is related to that invention described in copending European Patent Application 82305597 .
- the present invention is based on a realisation that, other things being equal, a measurable difference is achieved (a) if the effective level of mediator is altered (b) if the effective level of enzyme is altered, (c) if both are altered (d) if the effective surface area of the electrode changes; and is further based on the realisation that such alterations can be brought about by specific binding reactions between a ligand and an antiligand, in such ways that the measurable effect can be related back to the occurrence or extent of ligand/antiligand binding.
- the invention consists in a method of assay in which (a) at least one specific binding reaction stage between reactive species comprising a ligand and an antiligand is carried out in association with an enzyme/mediator system electrochemically linked to a level of a substrate to .which the enzyme is catalytically active so that the binding reaction affects the electrochemical availability of at least one of the components of said system and (b) the effect on the said electrochemical availability is detected or measured to give a signal from which the presence or amount of the said reactive species can be established.
- the procedures of the present invention involve the use of ligand and antiligand, e.g. antigen/antibody or D NA target sequence/DNA probe sequence; substrate; enzyme specific to the substrate; and mediator compound.
- ligand and antiligand e.g. antigen/antibody or D NA target sequence/DNA probe sequence
- substrate e.g. D NA target sequence/DNA probe sequence
- mediator compound e.g. enzyme specific to the substrate
- the specific binding reaction can take place wholly in solution i.e. be homogeneous, or can take place on a solid surface.e.g. can possibly be heterogeneous.
- the solid surfaces utilised in these procedures can include the wall of a containing vessel, or an electrode surface, and since such an electrode itself can be a simple carbon electrode or can be of gold or other noble metal (for example) or can be more or less complex with coatings of one or more of the various components, especially mediator, antibody or antiligand and enzyme but possibly substrate,there are many variant methods by which the invention defined above can be embodied. These methods, and their usefulness and advantages, will be set out, and exemplified in detail below.
- the enzyme/substrate pair are present merely as an indicator of the presence or extent of the specific binding reaction.
- they can be any such pair which is extraneous to the environment of the reaction, i.e. whose electrochemical or other action will not be confused with those of components naturally present in the total test mixture.
- the method chosen depends wholly or partly on reducing the enzyme level or electrochemical availability of enzyme (rather than wholly on mediator level) then the enzyme chosen should be such that the specific binding reaction affects that availability.
- Enzyme/substrate pairs whose electrochemical behaviour in association with mediator compounds have been studied by the Applicants include the following:-
- glucose enzymes have been carefully studied for test purposes relating to glucose sensing in vivo (e.g. for diabetic subjects). Enzymes such as the NADPH-independent glucose dehydrogenases e.g. as obtained from ⁇ cinetobacter calcoaceticus have been found valuable for this purpose, and can be used in the present invention. Glucose oxidase undergoes reactions which are well known and thus form a useful marker for the extent or occurrence of a specific binding reaction in accordance with the present invention. It is also stable in storage, industrially available and of low cost
- glucose oxidase While there is a some preference for glucose oxidase, the other enzymes listed above can be used with advantage in certain variant forms of the invention.In particular, the reaction speed of glucose dehydrogenase can be of value.
- the mediator compounds suggested for use in our prior Patent Applications listed above include polyviologens, chloranil, bromanil, etc, but are most preferably the compounds generally known as "metallocenes" and especially those which comprise at least two organic rings, each of which comprises a charge-conjugated system and a metal atom in electron-sharing contact with each of the said rings.
- Ferrocenes bis-cyclopentadienyl iron and its derivatives
- Ferrocenes have: (a) a wide range of redox potentials accessible through substitution of the cyclopentadienyl rings which can be functionalised; (b) electrochemically reversible one-electron redox properties; (c) the pH-independent redox potential and the slow autoxidation of the reduced form.
- the trend in E 0 values is in agreement with that expected on the basis of substituent effects.
- electron-donating groups stabilize the positive charge and hence promote oxidation more than electron withdrawing groups.
- a chemical linkage between either the ligand or enzyme and the mediator can be present in certain specialised embodiments.
- the following drugs may be combined with a mediator to configure an assay system capable of determining whether or not the concentration of the drug is within the preferred theraputic range:
- Ferrocene-modified electrodes can be prepared by a number of different techniques. The simplest procedure is to dope hydrophobic derivatives e.g. ferrocene, vinylferrocene and l,l'-dimethylferrocene on to a platinum or graphite surface by evaporation from a solution in an organic solvent. Alternatively, substituted derivatives can be covalently attached to hydroxyl functions on either carbon or platinum as below:
- a special case of such modification is to incorporate one or more thiol groups whereby ferrocene can link directly to gold electrodes, as described in more detail below.
- Electrode surfaces may also be coated with a functionalised polymer, polytyramine for example, to which substituted ferrocenes are covalently attached, as below
- vinylferrocene can be polymerised to give poly(vinylferrocene), (CH 2 -CHC S H 4 Fecp) n , which can be coated on to an electrode either by solvent evaporation or by electro-deposition
- the ferrocene carboxylic acids have been found to have an optimal combination of practical properties for general use in this invention, giving the possibilities of chemical linkages, as discussed below, through the carboxyl group(s) to the ligand, antiligand and/or enzyme.
- this consists in an assay system comprising;
- the invention consists in a method as described above in which an unknown amount of a ligand species to be determined is subjected to a specific binding reaction with a known amount, known to be in excess, of a species antiligand therefor itself chemically linked with the said mediator compound which antiligand species in its unbound state only is available for charge transfer from the enzyme/substrate reaction, whereby the subsequent electrochemical activity of the excess unbound mediator/antiligand species provides a measure of the amount of ligand species.
- the invention consists in a method as described above in which an unknown amount of a ligand species to be determined is subjected to a specific binding reaction with a known amount, known to be in excess, of a species antiligand therefor itself chemically linked with the enzyme which antiligand species in its unbound state only is available for an enzyme/substrate reaction, whereby the subsequent electrochemical activity of a mediator in transferring charge from unbound enzyme/antiligand species provides a measure of the amount of ligand species.
- ligand species is utilised to cover (a) an initial antigen or antibody i.e. as naturally occurring in or artificially stimulated to occur in, a human or animal subject, and presented either as a serum, whole blood, urine, interstitial fluid, cerebrospinal fluid or synovial fluid for assay or in wholly or partially purified form, or as a monoclonal antibody and (b) a partly reacted form or complementary derivative material from such an antigen/antibody e.g. as formed with a known amount, known to be in excess, of its own antiligand. For reasons of stability or availabilty of materials it may be preferred to work "stepwise" on the raw assay material until the unknown quantity is measurable in a convenient desired species.
- the invention is this form further consists in a method of homogeneous enzyme immunoassay which comprises:
- the enzyme, substrate and electrode can be made up and the stage (a) mixture added; or the stage (a) mixture can be formed within the liquid system of a pre-existing enzyme substrate mixture, and so on.
- stepwise procedures could be envisaged, provided that they reduce the unknown quantity to a form bindable to the mediator-linked material for eventual measurement.
- the man skilled in the art will not always expect the mathematical derivation to be simple subtraction: if one ligand/antiligand has several sites for binding, some distribution of binding can be expected and/or some equilibrium binding of different species.
- a valuable enzyme-substrate system is glucose/glucose oxidase.
- the invention consists in the method described generally above in which (i) (a) an unknown amount of ligand species X to be assayed and (b) an amount of a species X-E, in which X is chemically linked with an enzyme E without destroying the enzyme activity thereof, are mixed in solution (ii) the mixture is contacted with a substrate S for the enzyme and a mediator compound M in the presence of a sensor electrode to which a measured charge is thereby transferred in dependence on the enzymatically catalysed reaction (iii) antiligand A is contacted with the solution to set up competitive equilbrium binding reactions of the general nature of reactions I and II.
- the mediator M can be chemically linked to the ligand analyte X and can encounter the enzyme E and substrate S at step (ii), setting up a directly analogous competitive reaction in step (iii) i.e. one in which M is substituted for E throughout.
- A-X E + X -"
- a + X + X E
- A-X + X E, e.g. if a "dry strip" test for level of analyte X is to be developed.
- This comprises a method of immunoassay for a species X, which comprises:
- the amount of enzymatically active species is measured. It therefore lends itself to the further optional feature mentioned above and described in more detail below, in which the enzyme and mediator are themselves chemically linked.
- the invention consists in a method as described generally above in which at least one of the mediator and enzyme is chemically linked to a nucleic acid probe sequence whereby specific binding of the probe sequence to the target sequence in a single-strand nucleic acid material to be investigated affects the electrochemical availability of the chemically linked species as detected by a sensor electrode in presence of the enzyme substrate, whereby the presence of the target sequence can be detected.
- the nucleic acid sequence can be RNA e.g. messenger RNA but is usually DNA.
- this form of the invention consists in a method of detecting a target sequence in a nucleic acid material which comprises:
- the probe material can be a naturally occuring DNA fragment or a synthetically produced material.
- the sensor electrode itself can include the mediator or the enzyme, although generally it is preferred for the probe sequence and the target sequence both to be present in solution.
- the mediator can be linked indirectly to the probe sequence by a linker group, and a material reactive to the linker groups can be present on the electrode. In this case the whole complex is present on the electrode; when a target sequence is present, and binds to the probe sequence, an alteration in electrode current is produced.
- the invention consists in the method generally described above, which comprises immobilising a ligand to be assayed on a suitable surface; thereafter carrying out a specific binding reaction with excess of a suitable antiligand itself chemically linked to an enzyme, prior to removing the excess and adding a substrate for the immobilised enzyme; and contacting with a mediator and a sensor electrode, so that the charge transferred to the electrode is proportional to the amount of enzyme present.
- the above steps may be modified in their order, and the mediator may be present in the solution or on the electrode.
- the invention consists in the method generally described above in which the specific binding reaction takes place at the surface of a sensor electrode to block or alter the characteristics of the surface at least in part whereby the existence or amount of a decrease in detected electrical charge is a measure of the existence or extent of the specific binding reaction.
- the ligand immunologically reactive with the antiligand, can be any antigen arising in biochemical or medical testing as exemplified above.
- Their general nature as large protein-like molecules, appears to have the effect of blocking off part of the electrode surface when they react with the antiligand thereon. This causes a drop in current, the observation or extent of which indicates or measure the presence or level of ligand.
- the small bound nitroglycerine molecules probably would not block the electrode surface, but (especially in higher concentrations of antibody and/or nitroglycerine) may lead to conformational changes in the antiligand and thus changes in signal.
- the substrate material can in theory be any of the substrates listed in our various Patent Applications set forth above or listed herein, since any underlying enzyme/substrate reaction is of general applicability with such electrodes. However, it will be found convenient to use a simple, readily available, well-documented substrate and we prefer to use glucose for this purpose.
- the enzyme present on the electrode can similarly be any enzyme, especially those flavoprotein and quinoprotein enzymes listed above.
- the preferred substrate is glucose
- the preferred enzymes are glucose oxidase or glucose dehydrogenase e.g. as obtained from acinetobacter calcoaceticus. The latter is preferable to the former as having a hundred fold higher turnover number.
- ferrocene e.g. ferrocene
- concentration at which distortion of the molecule and loss of enzyme activity is observed e.g. ferrocene
- a glucose oxidase with about 8-12 ferrocene units is still enzymatically active and could be bound to carbon electrodes by methods known per se e.g. use of carbodiimide bonding.
- the modified enzyme is not only enzymatically active but also electrochemically active.
- the serum of a patient containing antigens (1) to be assayed is mixed with a solution of antibodies (2) of known strength in buffer.
- the antigen may, for example, be a drug.
- Antigens (1) in the serum bind to the solvated antibodies at specific antigen-binding sites (3), to form antigen/antibody complexes (4) Not all of the possible antigen-binding sites on the antibody are occupied and therefore a number of free binding sites (5) remain.
- the number of free sites is a function of the number of antigens (1) in the serum.
- a mediator-linked antigen (6) is added, in excess, to the mixture resulting from step 1.
- the mediator (7) is a ferrocene derivative which is chemically linked to the antigen (8), but it is envisaged that other metallocenes could be substituted.
- the ferrocene-linked antigen occupies the free sites (5) of the antibody (2) by virtue of an antigen/antibody binding reaction.
- the ferrocene-linked antigen (6) is present in excess over the number of free sites and therefore some of the ferrocene-linked antigen remains in solution (9).
- Glucose and glucose oxidase are added in excess to the mixture resulting and the current established by the redox action of GOD on glucose is measured with an electrode (E).
- GOD glucose oxidase
- E an electrode
- Only the ferrocene-linked antigen complexes (9) which are not bound to the antibodies (2) are able to electrochemically couple GOD to the electrode (11).
- the ferrocene-linked antigen complexes which are bound to the antibodies are prevented from coupling GOD to the electrode because of steric hindrance from the much larger antibody (2).
- the electrode (E) may be a made of gold, carbon, platinum or any suitable material.
- GOD and glucose may be replaced by the addition of any other enzyme/substrate pair providing that the particular mediator selected is capable of coupling the enzyme/substrate reaction to the electrode.
- the enzyme nor the substrate both present in excess
- the limiting factor is the amount of mediator which is freely diffusing when the free sites have been occupied.
- Total sample volume was 1 ml.
- Glucose oxidase- labelled T 4 Thyroxine and antibodies to T 4 thyroxine were supplied by Corning Glass Inc. (Medfield, Mass, U.S.A.).
- glucose oxidase(GOD) catalyses the conversion of glucose to gluconic acid and liberates electrons, e, which reduce a ferrocene mediator F from its oxidised to its reduced condition. Reduced ferrocene ion is oxidised at the electrode and the current passed is measured and is proportional to the amount of glucose present.
- Linked to the GOD by any suitable method is a DNA fragment D which may be either derived from a naturally occuring DNA sequence or may be synthetic.
- a redox-active substituted ferrocene F is attached directly(Fig. 3b) to the fragmented DNA which is to be used as a probe.
- the formation of mediator-linked DNA-probe does not impede either the amperometric response of the mediator F nor the binding interaction of the mediator-DNA probe with the complementary target sequence contained in the DNA which is being assayed.
- the amperometric response caused by the addition of the mediator-DNA probe to the assay mixture is measured. If genetic material in a single-stranded form to which the probe is complementary is present, the probe binds to the complementary sequence in the sample DNA. This greatly reduces or completely inhibits the amperometric response, that is, the complex of the mediator-DNA probe and the target DNA is not amperometrically active. The reduction in the initial amperometric response is in direct proportion to the amount of mediator-DNA probe/target DNA complex formed and hence to the amount of genetic material containing a sequence complementary to the known sequence of the mediator-DNA probe.
- the enzymatic activity is unchanged but the extent to which it is transferred to the electrode is altered.
- the ferrocene-DNA probe also contains one or more linker groups L , (biotin may for example be used).
- An electrode on whose surface is present an electrochemically active material R, that recognises the linker group L( for example avidin labelled with ferrocene) is then immersed in the reaction mixture. The current is measured on applying a potential
- the mediator-linker-DNA probe is now treated with the mixture of the single-stranded genetic material and the mediator-linker-DNA probe binds to any complementary sequence present.
- the original current is reduced on the binding of the electrochemically active material R to the mediator-linker-DNA probe /target-DNA complex.
- the reduction of the current is again in proportion to the amount of the added single-stranded sequence with a target sequence complementary to the known sequence of the DNA-probe.
- RNA deoxyribonucleic acid
- an antibody is placed in a polyester or polysytrene container (11), at which time some of the antibody (12) binds to the walls of the container.
- the container may be treated to enhance the binding of the antibody, and/or to prevent subsequent non-specific binding of antibody (12) as described below.
- This treatment to avoid or reduce non-specific binding can include the coating of the container (11) with Bovine Serum Albumen .
- An antigen sample is added at 12d, and binds to the antibody itself linked to the walls of the container.
- the antibody- linked enzyme in this example Glucose oxidase (15) linked to further antibody (12) is added, and the antigen/antibody binding reaction proceeds.To ensure binding, the antibodies may be different and bind to different portions of the antigen 12a.
- the container is washed to remove excess antigen-enzyme complex, and a solution containing a soluble ferrocene (16) is added together with an aliquot of glucose substrate.
- a reference electrode (17), such as a calomel, silver-silver chloride, gold, platinum or any other suitable noble metal electrode is placed in the solution together with an electron transfer electrode (8) which may or may not have an external coating of ferrocene.
- the current produced at the electrode (8) is read via line (19).
- the current is proportional to the activity of glucose oxidase 15 and therefore bears a stoichiometric relationship to the antibody glucose combination and hence to the sample antigen 12a to which this binds.
- the mediator could be antibody-linked, and the enzyme could be added with the substrate. Other variations are also possible.
- Ferrocenemonocarboxylic acid was coupled to glucose oxidase using isobutylchloroformate.
- the terminal amine of the protein was involved in the reaction with a carbonic anhydride of ferrocene.
- the reaction was performed as follows; to a stirred cooled (-8°C) solution of Ferrocenemonocarbocylic acid (lmM 235mg in 3ml of dry tetrahydrofuran), isobutylchloroformate (0.13ml) and triethylamine (0.14ml) were added with constant stirring. Care must be taken at this stage to keep the reaction water-free and prevent hydrolysis of the anhydride product. A drying-tube was attached to the apparatus which was otherwise sealed, and had been previously purged with Argon.
- the mixture was stirred for thirty minutes at -8°C, and then allowed to warm to room temperature and stirred for another hour.
- the resulting carbonic anhydride of Ferrocene was added dropwise to a cooled (2°C) solution of glucose oxidase (150mg in 50ml of 0.1M NaHC0 3 solution). As the Ferrocene was added the pH was maintained at 8 with 0.1M NaHCo 3 .
- the reaction mixture was stirred at 4°C for 24 hours and then centrifuged. This removed a large proportion of unreacted Ferrocene and any precipitated enzyme.
- the protein was then exhaustively dialysed against pH 8.5 borate buffer (0.2M boric acid, 0.05M borax, adjusted to pH with the latter).
- the iron content of the modified enzyme was determined by atomic adsorption. To determine the protein content, a spectrophotometric assay technique was used. The assay is based on the shift of absorbance from 465nm to 595nm of an organic dye. Coomassie Blue, on binding to the protein at acidic pH.
- a 20% aqueous solution of the dye was filtered.
- a standard solution (l.4mg/ml) of unmodified glucose oxidase was prepared and from this concentrations of glucose oxidase were mixed with the Coomassie Blue solution. Optical densities at 595nm were then meassured at each concentration of enzyme, and a standard curve obtained for the unmodified enzyme ( F ig. 4.2).
- the protein concentration of the modified enzyme can thus be estimated by finding the optical density of a sample and comparing it with the standard curve. In the sample prepared the protein concentration was found to be 11.04uM. The iron concentration was 87.5uM.
- Typical diffusion-control kinetics show that the ferrocene molecule (linked to the enzyme through an amide) acts as a reversible, one electron mediator and shows Type I kinetics.
- the second-order rate-constant, k, for the reaction between ferrocene and the reduced form of glucose oxidase was calculated as 3.5 x 10 5 m -1 s -1 .When this value is compared to the one obtained for solution kinetics of the same system (1.15 x 10 m -1 s -1 ) it is seen that modification causes an increase in the rate of reaction.
- the ligand may be (a) an immunologically active protein or polypetide chain (b) a hapten between 100-2,000 molecular weight. In the latter case antibodies may be raised to the hapten by conjugating the hapten to a protein (such as Bovine serum albumin) to render it immunogenic (c) a carbohydrate or other organic molecule which can be rendered immunogenic.
- a protein such as Bovine serum albumin
- ligands examples include:
- hapten Ligands include:
- electrochemical techniques may be used in determining the electrochemical change in the system e.g. differential pulse voltammetry, cyclic voltammetry, or square wave voltammetry. In order to minimise response times kinetic, rather than end point, measurements may be desirable.
- the thiol group can be directly or indirectly attached to one ring of the ferrocene structure, e.g. by a lower alkyl group containing 1 to 6 carbon atoms.
- the simple thiol (ferrocene) - SH can be used, prepared as in J. Chem. Soc. 692 (1958) Knox and Pauson.
- ferrocene alkyl thiols
- ferrocenyl thiobutane is valuable i.e. (ferrocene)-C 4 H S -SH.
- Other more complex thiol-like compounds are possible e.g. l,2,3-trithia-(3)-ferrocenophane in which the two rings are linked by a chain of sulphur atoms (a mixture of substances with different numbers of chain sulphur atoms is possible).
- the gold electrode can be prepared for repeated use e.g. by dipping into solutions of such compounds, so as to link the mediator ferrocene structure to the conductive metal.
- Ferrocene thiopentane Ferrocenyl thiobutane
- Foid (2) (12g) was dissolved in ether (distilled from sodium/potassium) and treated with lithium aluminium hydride (1.27g) in a nitrogen atmosphere. When reaction was complete the excess lithium aluminium hydride was destroyed using ethyl acetate and then water. The organic phases were separated and the aqueous phase washed with ether (2 x 20 ml). The organic phases were combined and dried (MgSO 4 and after filtration the solvent was removed on the rotary evaporator.The red oil resulting had two components. Column chromatography(30 cm x 2 cm) on silica eluted with 1:1 ether:hexane gave the alcohol and an ester,F c -CH 2 -CH 2 -CH 2 -CH 2 -COOCH 3
- Ferrocene is conjugated to the therapeutic drug of interest. In the absence of its antibody the ferrocene drug conjugate is free to mediate between glucose oxidase and the electrode. Excess glucose is used so that the enzyme is not substrate limited.
- the ferrocene-drug conjugate In the presence of its antibody the ferrocene-drug conjugate is bound to the antibody and the ferrocene is no longer free to mediate between the enzyme and the electrode. If, however, the unmodified drug is present in the sample, then it will be able to compete with the ferrocene-drug conjugate for its antibody - thus preventing the binding of the ferrocene conjugate, and leaving it free to mediate between glucose oxidase and the electrode.
- An ideal ferrocene labelled therapeutic drug of interest should not change the binding characteristics observed from the natural drug for its antibody, i.e. the antibody should bind the labelled drug as well as the unlabelled drug.
- the product had characteristic i.r. absorbances at 2240 cm -1 , (-CN stretch), 1002 cm -1 ferrocene (C-H) bend and 1108 cm antisymmetric ring pulsation. Its melting point was in the range 77-78°C.
- nitrile (6.20g) was dissolved in ethanol (100ml) and potassium hydroxide (18g) in water (150ml) added and the solution refluxed for 18 hours then cooled. The bulk of the solvent was removed on the rotary evaporator to a final volume of 100ml. This solution was extracted with ether (3 x 150ml) and the aqueous phase then filtered and acidified (to pH 3.0 using orthophosphoric acid, 85%). The yellow precipitate was filtered and dried (phosphoric oxide, desiccator) to give a yellow powder, 4.54g.
- Ferrocene acetic acid (5.1g) and 5,6-diamino-1,3-dimethyluracil hydrate (3.57g) were refluxed under nitrogen in dimethyl aniline (80ml) using a Dean-Stark apparatus. After 18 hours the solution was allowed to cool and aqueous sodium hydroxide solution (8%, 36ml) was added and the solution steam distilled. When complete the pot contents were filtered and then acidified using acetic acid to pH 4.5. The precipitate formed was filtered under suction and dried over phosphorous pentoxide in the vacuum desiccator.
- the i.r. spectrum has peaks characteristic of theophylline between 700 cm -1 and 800 cm -1 , and also between 1600 cm -1 and 1750 cm -1 and signals due to a ferrocene component substituted in one ring at 1000 cm -1 and 1100 cm -1 .
- the ferrocene theophylline conjugates III and VI were assayed to determine their antigenic character, using the Immunotech-double antibody enzyme immunoassay kit.
- This is a heterogenous enzyme immunoassay method that is based on the principle of competitive binding, where the theophylline ferrocene conjugate or a standard in a sample competes with a theophylline enzyme conjugate for a specific antibody.
- the separation step is achieved using double antibody immunoprecipitation. Enzyme activity is determined in the pellet and is inversely proportional to the theophylline concentration.
- Standard curves are normally presented as plots of either absorbance at 400nm or the absorbance of the sample expressed as a percentage of the blank versus the log of the concentration.
- a much more informative method is to perform a logit transformation of the data where:
- Logit %A/A o is then plotted versus the natural log of the concentration to yield a straight line. In order to examine the cross reactivity of a compound, their logit transformations should yield parallel straight lines.
- Glucose oxidase (EC 1.1.3.4) was supplied by Boehringer Mannheim. D-Glucose (AnalaR) was from BDH. All solutions were prepared from Aristar grade reagents (BDH) in high purity water (Millipore); supporting electrolyte was 0.1 M K 2 HP0 4 adjusted to the required pH with HC10 . .
- the d.c. cyclic voltammogram of the uncoupled reaction was then recorded using a scan rate of 5mV s -1 . Thereafter, 50 ⁇ l of a 3mg/ml solution of glucose oxidase was added, the solution degassed using argon, and the voltammogram of the enzyme catalysed regeneration of ferrocene from the ferricinium ion recorded. The final concentration of compound III was 24 ⁇ M.
- the voltammogram showed no reversible behaviour, with only an anodic peak at 240mV and no peaks at reducing potential. This peak was shown to be due to an unknown component in the antiserum itself.
- glucose oxidase no catalytic current was observed and indeed the voltammogram was identical to that of the uncoupled reaction, indicating that compound III had been completely bound to the antibodies such that it could not take part in electron transfer reactions at the gold electrode and could not act as a mediator for glucose oxidase.
- this assay could alternatively comprise a dry strip in which the theophylline/ferrocene conjugate, the theophylline antibody, glucose oxidase, glucose are placed on the active electrode so that at least the conjugate is separate from the antibody and the glucose oxidase is separate from the glucose (either by spatial location or physical state), and the above constitutes are one aspect of the present invention.
- a biological liquid containing an unknown theophylline level is added a competitive binding reaction is set up as described above and the current falls off as the assay progresses for measurement also as described above.
- the preferred configuration would be to set up a competitive binding reaction between on the one hand the ferrocene/theophylline to be assayed, for binding sites on the antibodies. To do this the following procedure is effected:-
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Applications Claiming Priority (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8312259 | 1983-05-05 | ||
| GB838312263A GB8312263D0 (en) | 1983-05-05 | 1983-05-05 | Immunospecific detection/assay |
| GB838312259A GB8312259D0 (en) | 1983-05-05 | 1983-05-05 | Enzyme-containing sensors |
| GB8312263 | 1983-05-05 | ||
| GB8312265 | 1983-05-05 | ||
| GB838312265A GB8312265D0 (en) | 1983-05-05 | 1983-05-05 | Chemically modified enzyme |
| GB838325316A GB8325316D0 (en) | 1983-09-21 | 1983-09-21 | Enzyme linked immunoassay |
| GB8325316 | 1983-09-21 | ||
| GB8333650 | 1983-12-16 | ||
| GB838333651A GB8333651D0 (en) | 1983-12-16 | 1983-12-16 | Nucleic acid sequence probes in amperometric biosensors |
| GB8333651 | 1983-12-16 | ||
| GB838333650A GB8333650D0 (en) | 1983-12-16 | 1983-12-16 | Homogeneous enzyme immundassay techniques |
| GB8401399 | 1984-01-19 | ||
| GB848401399A GB8401399D0 (en) | 1984-01-19 | 1984-01-19 | Electrochemical immunoassay |
| GB8405263 | 1984-02-29 | ||
| GB848405263A GB8405263D0 (en) | 1984-02-29 | 1984-02-29 | Electrode systems |
| GB848405262A GB8405262D0 (en) | 1984-02-29 | 1984-02-29 | Electrode systems |
| GB8405262 | 1984-02-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0125139A2 true EP0125139A2 (de) | 1984-11-14 |
| EP0125139A3 EP0125139A3 (de) | 1987-01-07 |
Family
ID=27576291
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP84303090A Withdrawn EP0125139A3 (de) | 1983-05-05 | 1984-05-08 | Spezifische Bindungsagenzein verwendende Testverfahren |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0125139A3 (de) |
| AU (1) | AU569076B2 (de) |
| CA (1) | CA1220818A (de) |
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| EP0150999A2 (de) * | 1984-01-26 | 1985-08-07 | Serono Diagnostics Limited | Testverfahren |
| EP0155135A2 (de) * | 1984-03-05 | 1985-09-18 | Serono Diagnostics Limited | Testverfahren |
| EP0167248A2 (de) * | 1984-07-06 | 1986-01-08 | Serono Diagnostics Limited | Testverfahren |
| WO1986005815A1 (en) * | 1985-03-25 | 1986-10-09 | Genetics International Inc. | Nucleic acid sequences attached to materials sensitive to magnetic fields, and methods of assay and apparatus using such attached sequences. |
| EP0223541A2 (de) * | 1985-11-11 | 1987-05-27 | MediSense, Inc. | Elektrochemische Enzymprobe-Verfahren |
| EP0278647A2 (de) * | 1987-02-09 | 1988-08-17 | AT&T Corp. | Enzyme verwendende elektrochemische Prozesse |
| US4840893A (en) * | 1983-12-16 | 1989-06-20 | Medisense, Inc. | Electrochemical assay for nucleic acids and nucleic acid probes |
| EP0351891A2 (de) | 1983-05-05 | 1990-01-24 | MediSense, Inc. | Aufgedruckte Elektroden |
| EP0470649A2 (de) | 1986-07-23 | 1992-02-12 | Unilever Plc | Verfahren und Gerät für elektrochemische Messungen |
| US5262035A (en) * | 1989-08-02 | 1993-11-16 | E. Heller And Company | Enzyme electrodes |
| US5262305A (en) * | 1991-03-04 | 1993-11-16 | E. Heller & Company | Interferant eliminating biosensors |
| US5264104A (en) * | 1989-08-02 | 1993-11-23 | Gregg Brian A | Enzyme electrodes |
| US5264105A (en) * | 1989-08-02 | 1993-11-23 | Gregg Brian A | Enzyme electrodes |
| FR2692357A1 (fr) * | 1992-06-12 | 1993-12-17 | Centre Nat Rech Scient | Antigène marqué par un système redox, procédé de dosage immunologique avec détection électrochimique et kit de dosage. |
| US5320725A (en) * | 1989-08-02 | 1994-06-14 | E. Heller & Company | Electrode and method for the detection of hydrogen peroxide |
| US5427912A (en) * | 1993-08-27 | 1995-06-27 | Boehringer Mannheim Corporation | Electrochemical enzymatic complementation immunoassay |
| US5516644A (en) * | 1991-07-29 | 1996-05-14 | Mochida Pharmaceutical Co., Ltd. | Electrochemical immunochromatographic assay |
| DE19622458A1 (de) * | 1996-05-24 | 1997-11-27 | Senslab Ges Zur Entwicklung Un | Enzymatisch-elektrochemischer Einschritt-Affinitätssensor zur quantitativen Bestimmung von Analyten in wäßrigen Medien und Affinitätsassay |
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| US5919642A (en) * | 1994-12-19 | 1999-07-06 | Boehringer Mannheim Corporation | Competitive binding assays having improved linearity |
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| US6949816B2 (en) | 2003-04-21 | 2005-09-27 | Motorola, Inc. | Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same |
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Cited By (200)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0351891A2 (de) | 1983-05-05 | 1990-01-24 | MediSense, Inc. | Aufgedruckte Elektroden |
| US4840893A (en) * | 1983-12-16 | 1989-06-20 | Medisense, Inc. | Electrochemical assay for nucleic acids and nucleic acid probes |
| AU578064B2 (en) * | 1984-01-26 | 1988-10-13 | Laboratoires Serono Sa | Direct enzyme monitor of enzyme linked assay |
| EP0150999A2 (de) * | 1984-01-26 | 1985-08-07 | Serono Diagnostics Limited | Testverfahren |
| EP0150999A3 (en) * | 1984-01-26 | 1986-12-30 | Serono Diagnostics Limited | Methods of assay |
| EP0155135A2 (de) * | 1984-03-05 | 1985-09-18 | Serono Diagnostics Limited | Testverfahren |
| EP0155135A3 (en) * | 1984-03-05 | 1989-02-08 | Serono Diagnostics Limited | Methods of assay |
| US4945045A (en) * | 1984-07-06 | 1990-07-31 | Serono Diagnostics Ltd. | Electrochemical methods of assay |
| EP0167248A3 (en) * | 1984-07-06 | 1986-12-30 | Serono Diagnostics Limited | Methods of assay |
| EP0167248A2 (de) * | 1984-07-06 | 1986-01-08 | Serono Diagnostics Limited | Testverfahren |
| WO1986005815A1 (en) * | 1985-03-25 | 1986-10-09 | Genetics International Inc. | Nucleic acid sequences attached to materials sensitive to magnetic fields, and methods of assay and apparatus using such attached sequences. |
| US4830959A (en) * | 1985-11-11 | 1989-05-16 | Medisense, Inc. | Electrochemical enzymic assay procedures |
| EP0223541A3 (de) * | 1985-11-11 | 1989-08-23 | MediSense, Inc. | Elektrochemische Enzymprobe-Verfahren |
| EP0223541A2 (de) * | 1985-11-11 | 1987-05-27 | MediSense, Inc. | Elektrochemische Enzymprobe-Verfahren |
| EP0470649A2 (de) | 1986-07-23 | 1992-02-12 | Unilever Plc | Verfahren und Gerät für elektrochemische Messungen |
| EP0278647A3 (de) * | 1987-02-09 | 1989-09-20 | AT&T Corp. | Enzyme verwendende elektrochemische Prozesse |
| EP0278647A2 (de) * | 1987-02-09 | 1988-08-17 | AT&T Corp. | Enzyme verwendende elektrochemische Prozesse |
| US5320725A (en) * | 1989-08-02 | 1994-06-14 | E. Heller & Company | Electrode and method for the detection of hydrogen peroxide |
| US5262035A (en) * | 1989-08-02 | 1993-11-16 | E. Heller And Company | Enzyme electrodes |
| US5264104A (en) * | 1989-08-02 | 1993-11-23 | Gregg Brian A | Enzyme electrodes |
| US5264105A (en) * | 1989-08-02 | 1993-11-23 | Gregg Brian A | Enzyme electrodes |
| US5262305A (en) * | 1991-03-04 | 1993-11-16 | E. Heller & Company | Interferant eliminating biosensors |
| US7462264B2 (en) | 1991-03-04 | 2008-12-09 | Abbott Diabetes Care Inc. | Subcutaneous glucose electrode |
| US6881551B2 (en) | 1991-03-04 | 2005-04-19 | Therasense, Inc. | Subcutaneous glucose electrode |
| US5516644A (en) * | 1991-07-29 | 1996-05-14 | Mochida Pharmaceutical Co., Ltd. | Electrochemical immunochromatographic assay |
| US6218134B1 (en) | 1991-07-29 | 2001-04-17 | Mochida Pharmaceutical Co., Ltd. | Process for specific binding assay for measuring the amount of analyte in a liquid test sample |
| US5710011A (en) * | 1992-06-05 | 1998-01-20 | Medisense, Inc. | Mediators to oxidoreductase enzymes |
| WO1993025907A1 (fr) * | 1992-06-12 | 1993-12-23 | Centre National De La Recherche Scientifique | Antigene marque par un systeme redox, procede de dosage immunologique avec detection electrochimique et kit de dosage |
| FR2692357A1 (fr) * | 1992-06-12 | 1993-12-17 | Centre Nat Rech Scient | Antigène marqué par un système redox, procédé de dosage immunologique avec détection électrochimique et kit de dosage. |
| US5427912A (en) * | 1993-08-27 | 1995-06-27 | Boehringer Mannheim Corporation | Electrochemical enzymatic complementation immunoassay |
| US6110696A (en) * | 1993-08-27 | 2000-08-29 | Roche Diagnostics Corporation | Electrochemical enzyme assay |
| US6013029A (en) * | 1993-10-09 | 2000-01-11 | Korf; Jakob | Monitoring the concentration of a substance or a group of substances in a body fluid |
| US5919642A (en) * | 1994-12-19 | 1999-07-06 | Boehringer Mannheim Corporation | Competitive binding assays having improved linearity |
| DE19622458A1 (de) * | 1996-05-24 | 1997-11-27 | Senslab Ges Zur Entwicklung Un | Enzymatisch-elektrochemischer Einschritt-Affinitätssensor zur quantitativen Bestimmung von Analyten in wäßrigen Medien und Affinitätsassay |
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| US6221238B1 (en) | 1996-05-24 | 2001-04-24 | Ufz-Umweltforschungszentrum Leipzig-Halle Gmbh | Enzymatic-electrochemical one-shot affinity sensor for the quantitative determination of analytes for aqueous media and affinity assay |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU569076B2 (en) | 1988-01-21 |
| EP0125139A3 (de) | 1987-01-07 |
| CA1220818A (en) | 1987-04-21 |
| AU2775384A (en) | 1984-11-08 |
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